Abstract The long-term goal of our research is to elucidate the neuroprotective mechanisms of 17E-Estradiol (E2) and selective estrogen receptor modulators (SERMs) and develop strategies for the discovery of suitable SERMs that can be used as neuroprotectants without risks of cancer for women or of feminizing effects for men. 17E- Estradiol (E2) has been shown to be neuroprotective in various neurodegenerative diseases such as Alzheimer?s disease (AD) and Parkinson?s disease (PD). Some SERMs, including tamoxifen (TX), also possess neuroprotective properties in the experimental models of AD, PD and ischemia. Although the mechanisms involved in neurodegeneration are incompletely understood, impairment of astroglial glutamate transporters is known to play a key role in the pathogenesis of various neurodegenerative diseases, including AD and PD as well as manganism (Mnism) caused by chronic exposure to manganese (Mn). Mn inhibits glutamate uptake and decreases glutamate transporter expression, which is vital in regulating extracellular glutamate levels. Though E2 appears to regulate astroglial glutamate transporter expression, the mechanism underlying E2 regulation remains elusive. Furthermore, TX and other SERMs, which are considered potentially therapeutically advantageous over E2 due to their lack or diminished negative side effects on the breast and uterus, unfortunately have not been examined to determine whether they exert potentially beneficial enhancement of astroglial glutamate transporter expression or activity, a deficit in the field that needs addressing. To address these gaps in our knowledge in this important area, we will use Manganism (Mnism) as an experimental model for impaired glutamate transporter-induced neurodegeneration, as Mn treatment is well established to induce impairment of glutamate transporters associated with neurotoxicity. Our central hypothesis is that E2 and TX can reverse Mn-induced inhibition of glutamate transporter activities by both modulation of transporter trafficking and by estrogen receptor (ER)-dependent expression of glutamate transporters via modulation of growth factors, in particular transforming growth factors (TGF)-D and TGF-E1. Our overall hypothesis will be tested in the following specific aims: 1) whether E2/TX reverses Mn-induced glutamate transporter inhibition by enhancing activity, expression and trafficking of the transporters, 2)whether E2/TX effects on glutamate transporters are ER-subtype dependent, 3) whether TGF- D and TGF-E1 mediate ER-dependent E2/TX-reversal of Mn-induced inhibition of glutamate transporters, 4) whether E2/TX treatment leads to neuroprotection against Mn-induced neurotoxicity in vivo by enhancing glutamate transporters. Our studies will provide novel insights into the mechanism(s) underlying the neuroprotective role of E2/TX in the model of Mnism and will offer potential insights into novel targets for treatment of a wide array of neurodegenerative disorders.